Progressive myoclonic epilepsies are a group of disorders characterised by a relentlessly progressive disease course until death; treatment-resistant epilepsy is just a part of the phenotype. This umbrella term encompasses many diverse conditions, ranging from Lafora body disease to Gaucher's disease. These diseases as a group are important because of a generally poor response to antiepileptic medication, an overall poor prognosis and inheritance risks to siblings or offspring (where there is a proven genetic cause). A correct diagnosis also helps patients and their families to accept and understand the nature of their disease, even if incurable. Here, we discuss the phenotypes of these disorders and summarise the relevant specific investigations to identify the underlying cause.
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The progressive myoclonic epilepsies comprise a devastating group of rare disorders that manifest with worsening action myoclonus; it is also present at rest but activates with stimuli such as noise, light or touch.1 Other neurological features that frequently but not reliably coexist include other seizure types (particularly generalised tonic–clonic), progressive ataxia and dementia. Typically, the presentation is in late childhood or adolescence; however, they may affect all ages. Ultimately, patients become wheelchair users and have a reduced life expectancy. It may be challenging to distinguish these conditions very early on from more common forms of genetic generalised epilepsy, particularly juvenile myoclonic epilepsy. However, features suggesting progressive myoclonic epilepsy are the presence or evolution of progressive neurological disability, failure to respond to antiepileptic drug therapy and background slowing on EEGs.2 Many progressive myoclonic epilepsies have similar clinical presentations yet are genetically heterogeneous, making accurate diagnosis difficult. Therein lies the importance of getting the diagnosis right: if we are to investigate specific treatments for individual disorders (eg, gene therapy for Tay–Sachs disease), then it is crucial to get the diagnosis right.3–6
Unverricht–Lundborg disease—also called progressive myoclonic epilepsy type 1 (EPM1)—is autosomal-recessively inherited and is characterised by stimulus-sensitive myoclonus and tonic–clonic seizures. The age of onset is usually 6–16 years. Some years after the disease onset, patients may develop cerebellar features, such as ataxia, incoordination, intention tremor and dysarthria. Individuals with Unverricht–Lundborg disease are mentally alert but show emotional lability, depression and mild decline in intellectual performance over time.7 EPM1 results from mutations in the CSTB gene causing defective function of cystatin B, a cysteine protease inhibitor.8
Lafora body disease
Lafora body disease—also called progressive myoclonic epilepsy type 2 (EPM2) and named after the Spanish neurologist Gonzalo Lafora—is an autosomal-recessive form of progressive myoclonus epilepsy. It is characterised by myoclonus, tonic–clonic seizures, visual hallucinations, intellectual decline and progressive neurological deterioration.9 The age of onset is usually 12–15 years, but an earlier onset variant begins at the age of 5 years.10 ,11 Lafora body disease is caused by mutations either in the EPM2A gene (encoding for laforin, a dual-specificity protein phosphatase) or in the EPM2B (NHLRC1) gene (encoding malin, an E3- ubiquitin ligase).11 These two proteins interact and, as a complex, regulate glycogen synthesis. Lafora body disease is, therefore, a disorder of carbohydrate metabolism resulting in polyglucosan inclusion bodies in neural and other tissues.12
Tissue biopsy (axillary skin) reveals Lafora bodies, which are aggregates of polyglucosans (poorly constructed glycogen molecules). Lafora bodies are pathognomonic and do not occur in any other condition.
Action myoclonus renal failure syndrome
Action myoclonus renal failure (AMRF) syndrome—also called progressive myoclonic epilepsy type 4 (EPM4)—is a distinctive form of progressive myoclonus epilepsy associated with renal dysfunction.13 It is an autosomal-recessive disease related to loss-of-function mutations in SCARB2 gene.14 The onset is in the second and third decades, but there is also a late-onset form, starting in the fifth and sixth decades and without renal failure.15 ,16 AMRF shows genotype–phenotype heterogeneity, such that affected people within the same sibship, despite identical gene mutations, can present differently: some with neurological features while others with renal impairment.17
PRICKLE1-gene-related progressive myoclonic epilepsy with ataxia
PRICKLE1-gene-related progressive myoclonic epilepsy—also called progressive myoclonic epilepsy type 5 (EPM5)—is characterised by myoclonic seizures, generalised tonic–clonic seizures (often sleep-related) and ataxia, but with normal cognition. The age of onset is 5–10 years. Action myoclonus may affect the limbs or bulbar muscles, sometimes with spontaneous myoclonus of facial muscles causing marked dysarthria.18 PRICKLE proteins, such as PRICKLE1, are core constituents of the planar cell polarity-signalling pathway that establishes cell polarity during embryonic development.19
‘North Sea’ progressive myoclonus epilepsy
‘North Sea’ progressive myoclonus epilepsy—also called progressive myoclonic epilepsy type 6 (EPM6)—is characterised by ataxia starting around aged 2 years and followed by myoclonic seizures when aged 6–7 years. Patients have multiple seizure types, including generalised tonic–clonic seizures, absence seizures and drop attacks. Most patients develop scoliosis by adolescence: an important diagnostic clue. There may also be skeletal deformities, including pes cavus and syndactyly. The condition is caused by mutations in the Golgi SNAP receptor complex 2 gene (GOSR2).20 Patients have elevated serum creatine kinase concentrations (median ≈700 IU) in the context of a normal muscle biopsy.21
Myoclonic epilepsy with ragged-red fibres
Myoclonic epilepsy with ragged-red fibres (MERRF) is a multisystem mitochondrial disorder, named after its characteristic muscle biopsy appearances (figure 1). The onset is usually in childhood, after normal early development. The first symptom is often myoclonus, followed by generalised epilepsy, ataxia, weakness and dementia. Common associated findings are hearing loss, short stature, optic atrophy and cardiomyopathy with Wolff–Parkinson–White syndrome. Some patients have pigmentary retinopathy and/or lipomatosis.22
Myoclonus does not occur in all mitochondrial diseases (3.6% of 1086 patients in one study) but is prominent in MERRF.23 Their myoclonus is not inextricably linked to epilepsy, but more so to cerebellar ataxia.23 MERRF is most commonly caused by a mutation in the tRNALys gene in mitochondrial DNA at nucleotide position 8344, leading to altered mitochondrial function, but there are also other point mutations.24 ,25
Neuronal ceroid lipofuscinoses
The neuronal ceroid lipofuscinoses (CLN) comprise a heterogeneous group of inherited, neurodegenerative, lysosomal storage disorders characterised by progressive cognitive and motor deterioration, progressive tonic–clonic as well as myoclonic seizures, and early death. Most forms have visual loss.26 The clinical phenotypes traditionally divide into infantile, late infantile, juvenile and adult, based on age at onset. However, a new classification system takes into account both the gene involved (genes designated with CLN loci from 1 to 14) and the age at disease onset; for example, (CLN1 disease, infantile onset) and (CLN1 disease, juvenile onset) are both caused by mutations in PPT1 but with differing age of onset, and with considerable phenotype–genotype heterogeneity (table 1).26 These are usually autosomal recessive but there are also autosomal-dominant late-onset forms.27 In childhood, the neuronal CLN are the most common lysosomal diseases and the most common neurodegenerative diseases, but, in adults, they represent a small fraction of the neurodegenerative diseases.28 The adult type (Kufs’ disease) is the rarest of all the subtypes of neuronal CLN. The pathological findings on biopsy are abnormal autofluorescent lipopigments from lysosomal inclusion bodies deposited in brain, myenteric plexus, muscle and skin. Electron microscopy has a special role in their diagnosis. The characteristic ultrastructural abnormalities in neuronal CLN, seen in conveniently available biopsy specimens (skin) or lymphocytes (buffy coat), include one (or a combination) of fingerprint, curvilinear and membranous profile inclusions in the lysosomes (table 1).29
Dentatorubral-pallidoluysian atrophy (DRPLA), unlike other progressive myoclonus epilepsies, is an autosomal-dominant disorder characterised by epilepsy, cerebellar ataxia, choreoathetosis, myoclonus, dementia and psychiatric symptoms in varying combinations. DRPLA is caused by an unstable expansion of CAG repeats in exon 5 of the DRPLA gene on chromosome 12, coding for polyglutamine tracts. Being a trinucleotide repeat disorder, it also shows the phenomenon of anticipation, with paternal transmission resulting in more prominent anticipation than maternal transmission. DRPLA protein (also called atrophin-1) is located in the nucleus and functions as a transcription coregulator.31 Patients with a progressive myoclonic epilepsy phenotype have larger expansions (62–79 repeats) and earlier age of onset (before aged 20 years) while those with a non-progressive myoclonic epilepsy phenotype have a later age of onset (after aged 20 years) and smaller expansions (54–67 repeats).32
Sialidosis type 1 (cherry-red spot myoclonus syndrome)
Sialidosis, also called mucolipidosis type I, is an autosomal-recessive lysosomal storage disease caused by a deficiency of the enzyme α-N-acetyl neuraminidase-1 (coded by the NEU1 gene on chromosome 6p21). It is classified into two main clinical variants: type 1, the milder variant, and type 2, usually more severe and with an earlier onset.33 The disease is characterised by myoclonic epilepsy, visual problems, hyperreflexia and ataxia that develop in the second or the third decade of life.34 Although patients with sialidosis always have macular cherry-red spots (figure 2), this is not a pathognomonic finding since they also occur in central retinal artery occlusion and metabolic storage diseases such as Tay–Sachs disease, Sandhoff's disease, Niemann–Pick disease, Fabry's disease and Gaucher's disease, some of which can also have a progressive myoclonic epilepsy phenotype.35 The characteristic pathology of sialidosis reflects tissue accumulation and urinary excretion of sialylated oligosaccharides.36
GM2 gangliosidosis (Tay–Sachs disease and variants)
The GM2 gangliosidoses comprise a group of autosomal-recessive disorders characterised by accumulation of GM2 ganglioside, one type of glycolipid, in neuronal cells. The genes responsible for these disorders are HEXA (Tay–Sachs disease and variants), HEXB (Sandhoff's disease and variants) and GM2A (AB variant of GM2 gangliosidosis).37 The proteins encoded by these three genes are the α-subunits (HEXA gene) and β-subunits (HEXB gene) of β-hexosaminidase A enzyme. The third is a small glycolipid transport protein, the GM2 activator protein (GM2A), which acts as a substrate specific cofactor for the enzyme. A deficiency of any one of these proteins leads to storage of the ganglioside, primarily in the lysosomes of neuronal cells, causing cell death.38 The three subtypes are clinically indistinguishable apart from subtle visceral and skeletal manifestations in some people with Sandhoff's disease.39 The most severe early onset form of Tay–Sachs disease is characterised by a progressive and relentless neuronal dysfunction, manifesting as hypotonia, blindness, dementia, seizures and subsequently death, usually by aged 3–5 years.40 Late-onset GM2 gangliosidosis shows a wide range of symptoms, including cerebellar ataxia, dystonia, motor neurone disease, psychiatric symptoms, dementia and rarely polyneuropathy.41
Gaucher's disease is the most prevalent lysosomal storage disease and is caused by >200 mutations that produce abnormal glucocerebrosidase.42 Gaucher's disease can have several phenotypes, ranging from a perinatal lethal form to an asymptomatic type.43 There are three major clinical phenotypes (1, 2 and 3). Only types 2 and 3 involve the central nervous system and are distinguished by age at onset and the rate of disease progression, but these distinctions are not absolute. Type 3 cases can cause several neurological impairments, including a horizontal gaze abnormality, progressive dementia, generalised epilepsy, ataxia and spasticity but also a progressive myoclonic epilepsy phenotype.44
Not all progressive myoclonic epilepsies have well-characterised neurophysiological findings, but we shall describe those of the most common disorders. Lafora body patients’ EEGs show varying degrees of slowing of background activity (in the vast majority), generalised epileptiform discharges (in 85%), focal discharges (in about a third) and photosensitivity to a fast-frequency stimulus (in a quarter). About two-thirds of patients show giant somatosensory-evoked potentials (14–175 µV) (figure 3).45
In Unverricht–Lundborg disease, the scalp EEG shows generalised epileptiform discharges in the majority of patients; about half of the patients show giant somatosensory-evoked potentials.45 In MERRF, EEG in about two-thirds of patients shows slowing of background activity with/without generalised epileptiform discharges; a minority show giant somatosensory-evoked potentials. There may be coexistent neuropathy or myopathy.45
In neuronal CLN, EEG shows varying degrees of diffuse slowing of background activity (in 95%) and generalised epileptiform discharges (in 80%); about a quarter of patients show giant somatosensory-evoked potentials. Nerve conduction studies show evidence of axonal neuropathy in about 30% of patients.45
Investigations should be directed towards the phenotype that best fits the patient's condition; however, the clinical phenotypes of the progressive myoclonic epilepsies overlap sufficiently such that it is not possible to make a definitive clinical diagnosis of individual disorders, and hence the reliance on laboratory, genetic and ancillary investigations. Some of the progressive myoclonic epilepsies are metabolic disorders such as Gaucher's disease and Tay–Sachs disease, and these can be diagnosed with white cell enzyme analysis; other conditions such as Lafora body disease and the neuronal CLN have characteristic histopathological findings on skin biopsy. Others such as AMRF syndrome and DRPLA can be diagnosed only with genetic tests (table 2).
There are specific treatments for some forms of progressive myoclonus epilepsy. For example, metabolic disorders such as Gaucher's disease may respond to substrate reduction therapy or enzyme replacement therapy. Enzyme replacement therapy is now considered the gold standard for the management of Gaucher's disease type 1 and for the non-neurological manifestations of Gaucher's disease type 3.46 For conditions where there is no specific therapy, such as Gaucher's disease type 2, clinicians can offer only symptom treatment with antiepileptic drugs to control seizures.
Valproate is often the first choice to treat myoclonic seizures because of its broad spectrum of antiepileptic action and its good myoclonus suppression potential. It may be less preferable in women owing to its teratogenicity but should not be denied to women who have no plans to conceive, in the face of an incurable disease. The rationale for using valproate to treat myoclonus in progressive myoclonic epilepsies is based on trials of its efficacy in juvenile myoclonic epilepsy, a myoclonic epilepsy with a comparatively benign prognosis.47 Sometimes valproate alone cannot achieve seizure control. Also, valproate should be avoided in MERRF due to concerns about liver failure when used in patients with other mitochondrial disorders.48 In a small trial of 26 adults with progressive myoclonic epilepsies, the combination of valproate, clonazepam and phenobarbital was superior to conventional antiepileptic drugs such as phenytoin, carbamazepine, primidone and diazepam.49 In fact, clonazepam is the only drug approved by the US Food and Drug Administration as monotherapy for the treatment of myoclonic seizures,50 but clobazam can be used for brief periods to control seizure clusters. Levetiracetam and topiramate are also highly effective for myoclonic seizures and are often used in combination or as second-line treatment. On the other hand, some antiepileptic drugs may exacerbate or even induce myoclonus51 and clearly should be avoided, particularly sodium channel blockers (carbamazepine, oxcarbazepine) and GABAergic drugs (tiagabine, vigabatrin), as well as gabapentin and pregabalin.7
Lamotrigine does not appear to be useful in progressive myoclonic epilepsies due to poor efficacy, dose-related exacerbation of myoclonus and putative late-onset worsening.52 Lamotrigine also may exacerbate myoclonus in non-progressive myoclonic epilepsy seizure states.53 ,54 The evidence for levetiracetam, topiramate and zonisamide in progressive myoclonic epilepsies comes from case series; these drugs may reduce myoclonus besides their efficacy in treating generalised tonic–clonic seizures.55–57
Despite all of the available antiepileptic drugs, clinicians should recognise a risk of overmedication in treating drug-resistant myoclonus. Generalised convulsive seizures are often part of the phenotype of the progressive myoclonic epilepsies and these are well controlled with classic antiepileptic drugs, whereas myoclonus—which can be the most disabling symptom resulting in the patient becoming wheelchair user—is usually refractory to standard antiepileptic drugs.59 It may be that the drug-resistant myoclonus is subcortical in origin.60
Progressive myoclonic epilepsies as a group are not amenable to surgical resection. Vagus nerve stimulation can help control epileptic seizures and status epilepticus, but will not help the myoclonus or cerebellar symptoms, and has no effect on cognitive impairment.61
The prognosis of this group of epilepsies is poor in terms of seizure control with antiepileptic drugs; however, the natural histories of the individual disorders vary. In the most devastating disorders, such as Lafora body disease, there is a progressive neurological deterioration beginning in adolescence, leading to a vegetative state in status myoclonicus and death within 10 years9 (table 4).
There are some forms of progressive myoclonic epilepsies that have yet to be clinically and genetically characterised. Although the progressive myoclonic epilepsies as a group may perhaps be the rarest of the inherited epilepsies, recent molecular genetic advances are unravelling the causes of previously nebulous entities such as AMRF syndrome. In time, the progressive myoclonic epilepsies may well become the best understood of the epilepsies at the cellular level, with the promise of specific treatments.
We thank Dr Graeme Williams, Consultant Neuro-ophthalmologist, Institute of Neurological Sciences, Glasgow, for the image of cherry-red spot in the retina.
Contributors All authors contributed equally to the paper.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed. This paper was reviewed by Reetta Kälviäinen, Kuopio, Finland.
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